Earlier studies provided evidence for a novel endothelial cannabinoid receptor mediating vasodilation in certain vascular beds (Offertaler et al., Mol Pharmacol 63:699-705, 2003; Begg et al., J Biol Chem 278:46188-94, 2003). In more recent experiments we found that a receptor with the same pharmacological properties mediates stimulation of endothelial cell migration, as quantified in a transwell chamber, and thus may be involved in angiogenesis. In cultured human umbilical vein endothelial cells (HUVEC), abnormal cannabidiol stimulates migration, an effect that is blocked by the compound O-1918, by pertussis toxin, or by PI3 kinase inhibitors, but not by CB1 or CB2 receptor antagonists. In CHO cells stably transfected with the EDG-1 receptor, sphingosine-1-phosphate, but not abnormal cannabidiol, stimulated migration. Thus, an endothelial receptor sensitivie to abnormal cannabidiol and distinct from CB1, CB2 or EDG-1 may regulate cell migration and angiogenesis. The endogenous ligand for this receptor remains to be identified. Our earlier studies implicated endocannabinoids and CB1 receptors in endotoxin (LPS)-induced hypotension (FASEB J 12:1035-44, 1998; J Biol Chem 278:45034-39, 2003). Recent evidence indicates the existence of cannabinoid receptors distinct from CB1 or CB2 which are inhibited by SR141716 but not by other CB1 antagonists such as AM251. In pentobarbital-anesthetized rats, i.v. injection of 10 mg/kg LPS elicits hypotension associated with profound decreases in cardiac contractility, moderate tachycardia and an increase in lower body vascular resistance. Pretreatment with 3 mg/kg SR141716 prevented the hypotension and decrease in cardiac contractility, slightly attenuated the increase in peripheral resistance and had no effect on the tachycardia caused by LPS, whereas pretreatment with 3 mg/kg AM251 did not affect any of these responses. The LPS-induced hypotension and its inhibition by SR141716 were similar in pentobarbital-anesthetized wild-type, CB1-/- and CB1-/-/CB2-/- mice. We conclude that SR141716 inhibits the acute hemodynamic effects of LPS by interacting with a cardiac receptor distinct from CB1 or CB2, which mediates negative inotropy and may be activated by anandamide or a related endocannabinoid released during endotoxemia. Anandamide and cannabinoid receptors have been implicated in the hypotension in various forms of shock and in advanced liver cirrhosis. Anandamide also activates vanilloid TRPV1 receptors on sensory nerve terminals, triggering the release of calcitonin gene-related peptide that elicits vasorelaxation in isolated blood vessels in vitro. However, the contribution of TRPV1 receptors to the in vivo hypotensive effect of anandamide is equivocal. We compared the cardiac performance of anesthetized TRPV1 knockout (TRPV1-/-) mice and their wild-type (TRPV1+/+) littermates and analysed in detail the haemodynamic effects of anandamide using the Millar pressure-volume conductance catheter system. Baseline cardiovascular parameters as well as systolic and diastolic function at different preloads were similar in TRPV1-/- and TRPV1+/+ mice. The predominant hypotensive response to bolus intravenous injections of anandamide and the associated decrease in cardiac contractility and total peripheral resistance (TPR) were similar in TRPV1+/+ and TRPV1-/- mice, as was the ability of the CB1 receptor antagonist SR141716 to completely block these effects. In TRPV1+/+ mice, this hypotensive response was preceded by a transient, profound drop in cardiac contractility and heart rate and increase in TPR, followed by a brief pressor response, which were unaffected by SR141716 and were absent in TRPV1-/- mice. These results indicate that mice lacking TRPV1 receptors have a normal cardiovascular profile and their predominant cardiovascular depressor response to anandamide is mediated through CB1 receptors. The role of TRPV1 receptors is limited to thhe transient activation of the Bezold-Jarisch reflex by very high initial plasma concentrations of anandamide. We examined the possible role of the endocannabinergic system in cardiovascular regulation in hypertension. In spontaneously hypertensive rats (SHR), CB1 receptor antagonists increase blood pressure and left ventricular contractile performance. Conversely, preventing the degradation of the endocannabinoid anandamide by an inhibitor of fatty acid amidohydrolase reduces blood pressure, cardiac contractility and vascular resistance to levels in normotensive rats, and these effects are prevented by CB1 antagonists. Similar changes are observed in two additional models of hypertension, whereas in normotensive control rats the same parameters remain unaffected by any of these treatments. CB1 agonists lower blood pressure much more in SHR than in normotensive Wistar-Kyoto rats (WKY), and the expression of CB1 is increased in heart and aortic endothelium of SHR compared to WKY. These findings indicate that endocannabinoids tonically suppress cardiac contractility in hypertension, and that enhancing the CB1-mediated cardiodepressor and vasodilator effects of endogenous anandamide by blocking its hydrolysis can normalize blood pressure. Targeting the endocannabinoid system offers novel therapeutic strategies in the treatment of hypertension.